PROJECT SUMMARY Nearly 30 million patients in the United States suffer from either type 1 or type 2 diabetes. Hypoglycemia is a common and potentially life-threatening side effect of diabetes treatment. Clinical implications of hypoglycemia include acute risk of cognitive impairment, seizure, cardiovascular events, brain damage or even death, as well as long term risks of accelerated dementia. The progressive loss of hypoglycemic awareness, hypoglycemic unawareness, impairs recognition of the early signs of low blood sugar, increasing the severity of acute complications and the need for hospitalization. Current methods for management of severe hypoglycemia include intravenous dextrose infusion or intramuscular injection of glucagon. However, these methods require that an emergency source of medication is always available near the patient, and necessitate reliance on caregivers who may not be well trained to administer these treatments. A closed-loop implantable drug delivery system (IDDS) that releases anti-hypoglycemic drugs precisely in response to low blood glucose levels, and is small enough to be implanted with minimal invasiveness, could substantially improve hypoglycemia management. The goal of this project is to develop novel technologies to make such an IDDS a reality. The proposed IDDS is the first ultrasonically powered implant platform for precision drug delivery that is minimally invasive and enables fully programmable, personalized, and closed-loop drug delivery to treat severe hypoglycemia. The IDDS utilizes electroresponsive polypyrrole nanoparticles (PPy NPs) to store the required drugs. When electrically stimulated, the PPy NPs change shape and size, thereby releasing their drug cargo. The IDDS is wirelessly powered using ultrasound which enables miniaturization of the implants for minimal invasiveness, and safe operation in the body. Closed-loop control will be implemented in order to release the drugs only when a low or rapidly falling glucose level is detected by a commercial glucose monitor. The objective will be reached by pursuing the following three specific aims: (1) Under Aim I, the size and composition of the nanoparticles will be optimized for efficient release of anti-hypoglycemic drugs. Our current models for enhancement of the stability of the drugs when attached to the nanoparticles will also be verified and optimized in vitro and in vivo in mouse models. (2) Aim II will entail development of the packaged mm-sized IDDS implant, integration of a commercial glucose monitor into the system, and in vitro validation of closed-loop functionality. (3) Under Aim III, in vivo tests in mice with induced hypoglycemia will be performed to optimize therapeutic reversal of hypoglycemia and subsequently with the integrated implant platform to test the feasibility of using the device to treat diabetic hypoglycemia. This project is significant as its successful completion could not only lead to a paradigm shift in how hypoglycemia is treated in the future, but also improve the treatment of other chronic diseases that require programmed, precise and localized drug delivery.